Alicyclic quaternary ammonium salts



Unite States Patent ALICYCLIC QUATERNARY AMMONIUM SALTS Charles F. Huebner, Morristown, N. J., assignor to Ciba Pharmaceutical Products, Incorporated, Summit, N. J., a corporation of New Jersey No Drawing. Application July 16, 1951, Serial No. 237,053

11 Claims. (Cl. 260-567.6)

This invention relates to new alicyclic quaternary ammonium salts and to the preparation thereof.

A primary object of the invention is the embodiment of a new group of compounds characterized by a potent curare-like activity and by freedom from undesired side efiects such as hypotension or respiratory paralysis.

This object is realized, according to the present invention, by a new group of alicyclic quaternary amines which correspond to the formula wherein R stands for a lower alkyl group, such as methyl, ethyl, propyl, butyl, etc., R stands for a lower alkyl group (which may be the same as or different from the lower alkyl group represented by R) or for an aralkyl radical, such as benzyl, alkylated benzyl, alkoxylated benzyl, halogenated benzyl, etc., X stands for a halogen atom as, for example, a chlorine, bromine or iodine atom, and n stands for one of the numbers 0, l and 2. These compounds fulfill the aforementioned desiderata in that, in addition to a high curare-like activity, they do not cause the aforesaid undesired side efiects. The new compounds are thus useful therapeutically, and may be administered intramuscularly, intravenously or orally.

A further object of the invention is the embodiment of efiicient methods for the preparation of the said alicyclic quaternary ammonium salts. This object is realized according to the present invention, for example by hydrogenating an appropriate amine of the formula wherein R may be H or lower alkyl, and n is one of the numbers 0, 1 and 2, until the phenyl rings are fully reduced, i. e. saturated. In those cases where R is H, the amino groups are then methylated, with the aid of a suitable methylating agent such as formaldehyde and formic acid. Where R is lower alkyl, such for instance as ethyl, propyl or the like, the fully reduced tertiary amines are obtainable directly on reduction according to this invention. In either case, the resultant saturated and alkylated product is then quaternized, with the aid for example of an appropriate lower alkyl halide such as methyl iodide, methyl chloride, ethyl bromide or ethyl iodide or of an aralkyl halide such as benzyl bromide or benzyl chloride.

The hydrogenation is, according to the invention, carried out at room temperature (about 20-30 C.) over a hydrogenation catalyst, which may be a noble metal such as platinum or palladium, in a solvent such as acetic acid, or over Raney nickel in alcohol at superatmospheric pressure and elevated temperature.

In certain cases, as in cases of especially convenient accessibility, other starting materials than the aromatic diamines can be employed. Thus, the intermediate of the formula H3C\ CHr-CE; CHz-CHz CH: NC\ CH-CHa-CH CH-N H3O GET-CH2 CHE-C CH3 can be prepared conveniently by the hydrogenation of CHz-CH: CHr-CH:

H:N-C CH-CHz-CHr-CH CHI-NH:

CHz- C 2 CHr-CHz is produced by the complete reduction of 4,4'-dinitrostilbene, the nitro groups being reduced to amino groups in the same operation which elfects the hydrogenation of the aromatic rings and of the ethylenic double bond; The respective intermediate is quaternized as previously set forth.

The following examples set forth representative exemplary embodiments of the invention, and these examples are intended to be solely illustrative and not at all limitative. In these examples, parts by weight bear the same relation to parts by volume as does the kilogram to the liter. Temperatures are expressed in degrees centigrade. Percentages are by weight. All melting points are uncorrected.

Example 1 100 parts by weight of benzidine:

in 1000 parts by volume of glacial acetic acid are hydrogenated at a temperature of about 20-30 and under a pressure of 50 pounds per square inch in the presence of 5 parts by weight of platinum oxide. When the theoretical amount of hydrogen for complete saturation has been consumed, hydrogenation is discontinued. Thereupon,

after removing the catalyst by syrup is dissolved in 100 parts by volume of water. The resulting solution is then made strongly alkaline with sodium hydroxide or potassium hydroxide and the water-insoluble free base (bicyclohexyl-4,4'-diamine) (3112-0112 0112-0112 HzN-C CH-OH CHNHI CHz-Ca CHz-C z which boils at ISO-160 is obtained.

10 parts by weight of the thus-obtained base are .dissolved in 50 parts by volume of ethanol, and 7.5 parts by volume of methyl iodide are then added to the solution. After standing for several hours at room temperature, ethyl acetate is added to complete the crystallization of the formed his quaternary salt. Recrystallization from a aqueous ethanol-ethyl acetate mixture gives the (bicyclohexyl) -4,4'-bis-(trimethylammonium iodide) which melts at 310-311 (with decomposition).

Methylation and quaternization of the crude primary hydrogenated base mentioned eaarlier in this example may be carried out alternatively as follows: 10 parts by weight of the base (bicyclohexyl-4,4-diamine) in parts by volume of acetone are stirred while refluxing with 27 parts by volume of methyl iodide and 25 parts by Patented Dec. 21, 1954 2,697,728 v V 4 'yveight of dry silver oxide for four hours. The solvent 1, last paragraph, yields ethylene-bis-[(4-clyclohexyl)-triis removed under reduced pressure and 'the quaternary methylammonium' iodide]:

salt extracted from the silver salts with 100 parts by vol- HSC CHTCHa CHrCH, CHa ume of 90% aqueous ethanol. On adding ethyl acetate to. the: hot solution until turbidity appearsa'nd cooling, CH'CHFCHTC (llzicyclrcalhexylhil-bis (tnimethylammonium iodide) is 330 I CHTCH, CHTCH, I 0 tame Example 2; which melts at 340 (with decomposition).

The compound; p,p-methylenedianiline',- of the forg q' ll s mula? 20 parts by weight of N,N,N,N-tetramethylbenzidene:

HN-Q-CIIg-QNH: is hydrogenated: and methylatedaccording to the pre- 1130/ scriptions of Example 1; usebeingimad'e ofan equivalent quantity (about 1081 parts by weight) of the said p,p.-methylenedianiline and. corresponding; amounts of the other reagents, whereupon the corresponding methylene-4,4'-bis(N,N-dimethyl cyclohexylamine)i: 2

in 200 parts by volume of glacial acetic acid are hydrogenated at a temperature of about 30 and a pressure of about 50 pounds per square inch in the presence pt 5 parts by wfeighgpf platinum oxidle; Wl gen the thflbrical i p amount 0 hy rogen or comp ete' s'a uration as 'efen C consumed, hydrogenation is discontinued, the catalyst is N-C CH0H=0 CH-N; filtered off, and the solvent removed'f'rom the filtrate; by H C g distillation. The residue isdissblved in jqpartsby vol:-

3 T- i 'f I 2 A 3 ume of w'ater' and the solution-made strongly basic w th; which'zboilsat 130 140. ata pressure of 0.2 millimeter, is sodium hydroxide or potassium hydroxide. The formed obtained. free base is' then extractedfrom'the s'olutionjwithtlie aid Quaternization of the thus-obtained product, in accordof n-butanol; After removal of the'n-butanolby distiliafance with the quaternizationprescriptions set forth in Extion from the obtained extractg'th'e' residual basemay" b'e ample 1, yields methylene-bis-[(4-cyclohexyl)-trimethy1- directly used for further reaction. v k ammonium iodide]: 5 pirts by weig%1tbof tl i1ebsaid base are trleated 3.5

H C CH CH CH CH CH parts y weight 0 er izy ro'n'iide; aftert e manner e- 3 2- 2* B 3 scribed [1n connection with methylene-'4;4'-b1s-(NgNuiia 2 ETC 2 3 39 ethanol-ethyl acetatemixture td yield b cyclohexyl-4;4- which g v 2 g1 w decompositibn). b1s-'(benzyldunethylammomum bromide):

1 part yweigh't. of the above quaternary ammonium 1 v salt is shaken for 12 hours with 5 parts by weight of H CHPCHK I freshly prepared :SllVCLChlOl'ldC. The silversalts are redo 11:0;N-0g /CH- j CH-N CH3. moved and'the aqueous filtrate concentrated-to dryness. magma l CHZQJHZ \cfikc Bi The non-crystalline metliylene-bisfl4-cyclohexyl)-triiflb i t i t tg chlonde] thus tamed freely which melts at 278479" (With dcomi osiii6ii);., V,

' 5 parts by weight of the hydrogenated b'aseobtained as v Example 3 described in this-exam'pIe are refluxed-mmmpaitssy 10 parts by weight of methylene-4,4'-bis-(N,N-diweight of p-methoxybe'nzyl'brdinide' in 25 parts by vanguamethyl-cyclohexyl-amine) obtained as described in Exof ethanol for 15" minutes Additiodof ethyl acetate ample 2 are refluxed. for 15 minutes with 9 parts by volcauses the quaternary salt to s'pziratein'a crystall'iiiecorb ume of benzyl bromide in parts by volume of ethanol. dition'; Recrystallizationfr'orn at-"90%" aquediisethanol- Eth-yl acet-ate' is addedtothe'cooled'solution until crystal 50 ethyl acetate mixture yields biyclohexyl-4',4f-l5is-(pi-med? lization occurs." Recrystallization" from" ethanol-ethyl oxybenzyldimethylam'rironium 'bromide) of tlie'fo'rmula HsC" CHE-"CH2 CHz-CHz /CH: HsC7lTI-CE /CH-'C\ /CH-'III CH= onto-@1120 Br CHz-CH: chi-om Br chi-@ocn; acetate; yields methylene-bis-lbenzyl- (.4-clyclohexyl) -di- Eitamp'l 6 methylammmum' bmmldel 20 parts by weight of 4, t"-bis-(dinithyl'aniind) beriiiifl HaC CHz-CEz 1 OKs-C32 /CH's phen'one; HiC N-C on-onz-ofi' cH-N-om H I g 3 H5C6H2C Br CHz-G i out-o 1 Br CHnCoHb which melts at 153 (with decomposition). 5 1150/ E l 4 t i are hydrogenatedtosaturatiom n glacial'aceticacid'and" compound, 4,4 'dmltrost'llbeflei 0f the formula? in the presence of platinurn oxide; after the prescriptions:

of Example 5, and the hydrogenatedbase re'c'overed as- OEBPQCEbCH-QNW described in the latter.

The samebas e'is'obtained by subieGting ZQ' parts by is. hydrogenated and methylated according'to the prewelght 0f -3' S-'(N;N=d1methyl=cyclohexyb" scriptions ofi Example"1,-usin'g-an equivalent quantityi- I (about.163'partsby'weight) of the'-'4,4'-dinitrostilbene and 1130- v 0'1'1; corresponding amounts of the other reagents, whereupon 7 H ethylene-4,4'-bis-(N,N-dimethyl-cyclohexylamine): c

mo /CHI-CH2 CHz-CH: /CH3 Hi0 N-CH Cmcm-om-c CH-N 4 to-hyl ldrofgenlation uhdi the"sa{)ne"-'co'nditions. Au f qual i' v. godweig to pa ladium oxi emay esubstituted for the p'lati H30 CHQ'C num oxide with-the same results. which'boils-at -180 at"0.'-2-' millimeter pressure; is n the s b e anequlvalqnt qu y obtaineda; of methyl iodide gives methylene-bis-[(4-cyclohexyl)-tri- Quaternization of the thus-obtained product with v methylammonium iodide], identical with the product obmethyl'iodide according to the prescriptions of Example 86 -ta1ned according to Example 2.

Example 7 5 parts by weight of the hydrogenated base: HsC CH2-CH2 CH:CH2 CH: N-C CH-CHr-Cfi CH-N 1130 CHr-Cz CHPCQ: CH3

as obtained in Example 6 are dissolved in 25 parts by weight of ethanol, and the solution treated with parts by weight of ethyl iodide. After allowing the thus-treated solution to stand for several hours at room temperature, ethyl acetate is added to complete the crystallization of the formed quaternary salt. Recrystallization of the latter from ethanol ethyl acetate yields methylene-bis-[(4- which melts at 257-258 (with decomposition).

Example8 The 20 parts by weight of 4,4'-bis-(dimethylamino)- benzophenone of Example 6 are replaced by an equivalent quantity of 4,4-bis-(diethylamino)-benzophenone, while otherwise proceeding to the production and recovery of a hydrogenated base according to the prescriptions of the said example. Reaction of the thus-prepared hydrogenated base with the corresponding amount of ethyl iodide, and recrystallization from ethanol of the thusproduced quaternary salt yields methylene-bis-[(4-cyclohexyl)-triethylammonium idoide] which melts at 238-240 (with decomposition).

By replacing the ethyl iodide, used in the preceding paragraph, by a corresponding quantity of methyl iodide, and otherwise proceeding as described in the said paragraph, there is obtained the corresponding methylene-bis- [(4-cyclohexyl) -diethylmethylammonium iodide] which melts at 256-257" (with decomposition).

Methylene bis [(4 cyclohexyl) diethylmethylammonium iodide] may be prepared alternatively as folows:

10 parts by weight of the base obtained by the hydrogenation of p,p-methylenedianiline as described in Example 2 are dissolved in 100 parts by volume of ethanol containing 13.3 parts by weight of freshly distilled acetaldehyde and 5 parts by volume of acetic acid. The mixture is hydrogenated in the presence of 0.5 part by Weight of platinum oxide at 50 lbs./ square inch pressure. After completion of the hydrogenation, the free tertiary base is recovered as described in Example 5. On reaction with methyl iodide, methylene-bis-[(4-cyclohexyl)-diethylmethylammonium iodide] is obtained, which melts at 256-257 (with decomposition).

"6 ing bicyclohexyl 4,4 bis (diethylmethylammonium iodide): H5O: CHz-CH: CzHs H5C2NOH CH-C CHNC2H5 H3O I CHPC! GET-C 0H; which melts at 299-300 (with decomposition).

Example 10 In lieu of the benzidine employed in Example 9, an equivalent quantity of p,p-methylene-bis-(N,N-diethylaniline) is hydrogenated under the conditions set forth in the said example. The catalyst is removed from the solution by filtration, and the alcohol is removed from the solution by distillation. The residual hydrogenated base is reacted with methyl iodide under the conditions set forth in Example 1. The thus-obtained methylene-bis- [(4-cyclohexyl) -trimethylammonium iodide] CHz-CH:

melts at 260-261 (with decomposition).

By reacting the hydrogenated base of the preceding paragraph with benzyl bromide, after the manner de scribed in Example 3, there is obtained methylene-bis- [benzyl-(4-cyclohexyl) -dimethylammonium bromide] which melts at 257-258 By refluxing 1 part by weight of the hydrogenated base of the first paragraph in this example with 0.95 part by volume of benzyl chloride in 10 parts by volume of ethanol for 12 hours and adding ethyl acetate to the solution, there is obtained methylene-bis-[benzyl-(4-cyclohexyl)- dimethylammonium chloride] in a syrupy state. By redissolving in alcohol, precipitating with ethyl acetate several times and drying, the quaternary amine salt is obtained in a non-crystalline form. It is freely soluble in water and has the formula:

5 parts by weight of the hydrogenated base obtained as described in Example 10 are refluxed with 6.1 parts by weight of p-chlorobenzyl chloride in 25 parts by volume of ethanol for four hours. Eethyl acetate is added to precipitate the non-crystalline methylene-bis- [p-chlorobenzyl- (4-cyclohexyl -dimethylammonium chloride] To 1 part by weight of the latter substance, dissolved in 5 parts by volume of ethanol, is added 1 part by weight of sodium iodide in 50 parts by volume of ethanol. The crystalline iodide immediately separating is filtered, washed with a small amount of water to remove the sodium chloride and recrystallized from water to yield methylene bis [p chlorobenzyl (4 cyclohexyl)- dimethylammonium iodide], which melts at 197-200" (with decomposition) of the formula:

CHz-CH: ore-cm on; mo N-o CHCH2C\ CHNl CHa 01-01110 i oar-on, 011F062 1 CHI-O01 Example 9 Having thus disclosed the invention, what is claimed is: l. A bis quaternary ammonium salt which corresponds 100 parts by weight of benzidine in 500 parts by volume to the formula wherein R stands for a lower alkyl group, R stands for a member selected from the class consisting of lower alkyl and aralkyl groups, X represents a member selected from the group consisting of chlorine, bromine and iodine, and n stands for one of the numbers 0, 1 and 2.

v2. (Bieynlohexyl) 4-,4 his (trialkylammonium Ital ide), the several alkyl groups being lower alkyl, and the halogen atoms having an atomic weight between about 35 and about 127.

3. Methylene bis 4 'eyclohexyl) -trialkylammoniurn halide], the several alkyl groups-being lower alkyl, and the halogen atoms having an atomic weight between about 35 and about 127.

4. Ethylene bis [(4 -cyclohexyl) trialkylammonium halide], the several alkyl groups being lower alkyl, and the halogen atomshaving an atomic weight between about 35'and about 1-27.

5. (Bieyclohexyl) 4,4 bis (at'alkyldialkylamrnonium halide), the several alkyl groups being lower alkyl, and flie'halogen atoms having an atomic Weight between about 35 and about 127.

5. Methylene bis '[aralkyl ('4 eyclohexyl) dialkylammonium halide], the several alkyl groups being lower alkyl, and the halogen atoms having an atomic weight between about 3'5 and about 127. p

7. '(Bicyclohexyl) 4,4 bis (trimethylarnmonium iodide). V

8. Methylene bis [(4 cyclohexyl) trimethylammo'nium iodide].

9. :Ethylene bis [(4 cyclohexyl) trimethylammoniurn iodide].

10. Bicyc1ohexyl 4,4 bis benzyldim'ethylammoium bromide).

11. Lower alkylene bis-[(4-cyclohexyl)-tri lower alkyl ammonium halide].

No references cited. 

1. A BIS QUATERNARY AMMONIUM SALT WHICH CORRESPONDS TO THE FORMULA 